negative regulation of amyloid-beta formation

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of amyloid-beta formation. [GOC:hjd, GOC:TermGenie, PMID:22992957]

Negative regulation of amyloid-beta formation is a complex biological process involving multiple molecular mechanisms aimed at reducing the production and accumulation of amyloid-beta (Aβ) peptides, which are implicated in the development of Alzheimer's disease. This process encompasses a wide range of cellular activities, including:

1. **Regulation of Amyloid Precursor Protein (APP) Processing:** APP is the precursor protein from which Aβ is derived. Negative regulation can occur at various stages of APP processing:
- **Decreased APP Production:** Transcriptional and translational regulation of APP gene expression can lead to reduced production of the precursor protein.
- **Increased α-Secretase Activity:** α-Secretase enzymes cleave APP within its Aβ domain, generating soluble fragments that do not form Aβ. Increased α-secretase activity promotes the non-amyloidogenic pathway of APP processing.
- **Decreased β-Secretase Activity:** β-Secretase (BACE1) initiates the amyloidogenic pathway by cleaving APP within its Aβ domain. Reducing BACE1 activity inhibits the production of Aβ.
- **Increased γ-Secretase Activity:** γ-Secretase cleaves APP at the C-terminus, releasing Aβ peptides. Although increasing γ-secretase activity might seem counterintuitive, it has been shown that certain modulators of γ-secretase can lead to the production of shorter, less amyloidogenic Aβ species.

2. **Aβ Clearance and Degradation:**
- **Enhanced Aβ Degradation:** Enzymes like neprilysin, insulin-degrading enzyme (IDE), and plasmin can degrade Aβ peptides. Up-regulating their activity can contribute to Aβ clearance.
- **Increased Aβ Clearance from the Brain:** The brain's lymphatic system, known as the glymphatic system, plays a crucial role in Aβ clearance. Enhancing glymphatic activity can improve Aβ removal from the brain.
- **Aβ Aggregation Inhibition:** Chaperone proteins and other molecules can prevent Aβ peptides from aggregating into toxic amyloid fibrils, thereby reducing their damaging effects.

3. **Modulation of Cellular Signaling Pathways:**
- **Inhibition of Tau Phosphorylation:** Tau protein hyperphosphorylation is associated with Alzheimer's disease and can contribute to Aβ aggregation. Inhibiting Tau kinases and promoting Tau dephosphorylation may indirectly impact Aβ formation.
- **Activation of Neuroprotective Pathways:** Certain signaling pathways, such as the Wnt pathway, are known to promote neuronal survival and may play a role in protecting against Aβ-induced toxicity.

4. **Immunological Mechanisms:**
- **Aβ Immunization:** Active or passive immunization strategies using antibodies against Aβ can target and clear Aβ peptides from the brain.
- **Microglial Activation:** Microglia, the brain's resident immune cells, can engulf and degrade Aβ. Regulating microglial activity to promote Aβ clearance is a potential therapeutic target.

These are some of the key aspects of negative regulation of amyloid-beta formation. Understanding these intricate mechanisms is crucial for developing effective therapies for Alzheimer's disease.'
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Proteins (6)

Compounds (338)